Materials for treatment of neurosyphilis and process of manufacture



Patented Dec. 13, 1932 UNITED STATES PATENT OFFICE PAUL J'. HANZLIK, OF SAN MYATEO, CALIFORNIA, AS SIGNOR TO THE BOARD OF TRUSTEES 7 OF THE LELAND STANFORD JUNIOR UNIVERSITY MATERIALS FOR TREATMENT .OF NEUnosYrHILIs AND rEooEss OF MANUFACTURE No Drawing.

This inventionrelates to anti-syphiliti 0 materials and particularly to remedies for the treatment and prevention of neurosyphilis. This application is a continuation in part of my application, Serial No. 436,889, filed March 18, 1930. I

It is now accepted that neurosyphilis begins at the time of acute syphilis and that the tie sirable mode of attack is to begin the treatment of neurosyphilis at the time of treatment of acute syphilis. The brain and central nervous'system are not easily penetrated and but few known chemicals such as methenamine, ethyl alcohol, iodides and bromides can enter into the brain and central nervous system to affect them. In accordance with the present invention, a material has been produced which-is an effective remedy for the treatment of acute syphilis and wbich'also can enter into the brain and central nervoussystem so that the treatment of neurosyphilis can begin at the time of treatment of acute syphilis. 7

The commonly used anti-syphilitic drugs cannot be depended upon to penetrate the cen-. tral nervous system without some previous treatment of the patient to increase the chi ciency of penetration. Obviously, if a drug could penetrate unaided, the treatment would. have decided advantages. I have-observed that anti-syphilitic drugs employing bismuth contain the bismuth iii-cationic form. The literature, of such character that it can be relied upon, denies the presence of bismuth in the cerebrospinal fluid, after the injection of compounds of this type and this fact I have confirmed. a

Previous bismuth compounds containing the bismuth as cations and used for the treatment of syphilis include bismuth metal in an aqueous dextrose solution 6%) ,bismuth salicylate in oil such as liquid petrolatum, and bismuth potassium tartra-te in oil. These compounds do not enter into the cerebrospinal fluid readily, it at all. Also their injection and use is attended with pain and discomfort and when bismuth sodium tartrate dis solved in a cane sugar solution (25%) is used, a local anaesthet c as benzyl alcohol (4%) 1s added'to the compound to reduce the pain;

Serious consequences to the patient sometimes Application filed September 29', 1930. seriaino. 485,305.

result because of the vehicle in which they are injected intramuscula-rly being handled by the body with difiiculty. For example, liquid petrolatum is not absorbed the body, being carried off only with difficulty mechanically. Tumors have occurred at the point of injection following continued use. i l

I have determined that bismuth when pres ent in' acid or anionic form is capable of penetrating the brain. Particularly I have determined that the sodiumsalt of bismuthic acid-NaBiO is capable of entering into the brains of animals. This compound is practically insoluble in all ordinary solvents and,'after injection, remains as an unabsorb-. able depot. ent invention other bismuth compounds, in which bismuth is'present in anionic form, have been prepared particularly salts of a haloid bismuthous acid such as iodo-bismuthous acid. Other halogen containing salts such as the chlorand the brombismuthites have been prepared. The term salt as employed herein is intended to include such inorganic salts as the sodium, calcium, ammonium, and sodium phenyl salts of the acid and also the organic salts or esters such as the acetyl, benzoyl, benzyl and sulphocyan. All of these materials have been prepared and contain anionic bismuth.

The method ofpreparation of thepreferred material, sodium iodobismuthite, is relatively simple While the compound secured is relatively pure and of a good yield. By way of example only, and for the sake of brevity, I will detailthe preparation of sodium iodobismuthite. The other compounds mentioned can be prepared by a similar process, such changes being made as are within the skill of the chemist making them. This salt is prepared by the the addition. of dry sodium iodide to a saturated solutioni ofbismuth chloride or bismuth iodide in a suitable solvent such as an hydrous ethyl acetate until the reaction is complete, the dry sodium iodide being in slight excess. I

While the reaction proceeds at room tem perature I have found that heating the mixture on a Water'bath with a reflux column In accordance with the pr'esattached, hastens the reaction and enables a more uniform product to be secured. Thus, for example, a constant rate of, and a more complete, reaction is secured as against the indeterminate rate under the fluctuating room temperatures.

, When the reaction is complete, insoluble sodium chloride and any excess of unreacted iodide are filtered off and the filtrate concentrated to a syrupy mass of crystals. Remaining liquor is filtered off on a Buchner funnel andthe crystals washed with ether several times.

It has been my observation that due to the formation of acetic acid upon hydrolysis of the ethyl acetate and to the presence of hydrochloric acid in the bismuth'chloride, impurities such as NaBiL, HBiI and HI are possibly present in the final product. These make the substance, when injected into a patient, slightly irritating and by washing with a suitable solvent, the impurities are removed from the crystals. Ether is preferred as the wash liquor since the sodium iodobismuthite is less soluble in it than in other solvents such as ethyl alcohol; The crystals of this salt are monoclinic with a brilliantred color. Several iodobismuthites are possible but my experience so far has been limited to the crystals separating out from alcohol, and those secured as above. The analysis of the purified crystals gives the formula Na BiI GH' O with abismuth content of 21.5 per cent by analysis. The sodiumiodobismuthite is 'hydr-olized and precipitated when in dilute'solution but it is possible to form concentrated solutions with water.

For the purpose of injecting the material I prefer that ethylene glycol, commonly termed glycol, be employed since I have found that this'material overcomes generally all the objections to previous vehicles. The crystals of the material are dissolved in cold ethylene glycol until a-concentration of 6%: is secured and the resulting solution, when injected intramuscular-1y, leaves a very slight yellowish precipitate, if any, and is practically non-irritating. The injection of an aqueous solution causes precipitation of the salt in the muscles with pain and irritation and irregular absorption. Glycerol may be also gmployed although its injection is more painul. 7

Other solvents, beside water and glycol, for iodobismuthite, are propylene glycol, glycerol, alcohol and ethyl acetate but of these solvents only the propylene glycol and glycerol ofi'er possibilities as vehicles for human injection. Under certain circumstances the use of propylene glycol which, while not possessing all the advantages mentioned in connection with the injection of ethylene glycol, will not possibly give rise to oxalate or the formation of calculi, as may the use of ethylene glycol in very large and toxic doses. This possible disadvantage of ethylene glycol has been carefully investigated and while in no way a serious one, since it does not occur with the therapeutic doses of ethylene glycol 7 used with iodobismuthite, the possibility is removed by propylene glycol.

A glycerol solution can be employed but not without discomfort to the patient. The injection of glycol is no more objectionable to the patient than the introduction of the needle alone, the material being very mobile, spreads easily and evenly, is easier to handle, more antiseptic and apparently less toxic than glycerol. The glycol solution has been successfully used without undue discomfort to the patient or without the appearance of systemic toxicity or other undesirable symptoms, as with previous vehicles. Glycol also does not require the giving of a local anaesthetic at the time of injection and is absorbed by the body.

It is my observation that the iodobismuthite is apparently in combination with the glycol since the bismuth compound can be distilled, and, after extracting with chloroform or ether and evaporation of the chloroform or ether. of the extract, a reddish brown residue remains behind containing the organic compound. I have found that the precipitation of iodobismuthite upon injection due to hydrolysis is prevented by adding an iodide as sodium iodide to the glycol. Potassium iodide can be employed if desired. In life experiments on guinea pigs the use of 10% sodium iodide with iodobismuthite in glycol gave slight precipitation at the site of injection in some animals but the use of 12% showed no evidences of precipitation and therefore 12% has been adopted and used successfully.

The penetration of the brain by the material has been demonstrated mainly with guinea pigs and rabbits injected with doses falling within the therapeutic range. The

results secured differ from most results of the literature which have been previously obtained with toxic and fatal doses of other bismuth products. Of forty one guinea pigs receiving therapeutic injections over periods ranging from five to thirty nine days 38 or 92.7% showed'the presence of bismuth in the brain and blood. The amounts demonstrated range from about 0.003 to 0.7 milligrams bismuth per 100 grams of brain. Of eight rabbits receiving subtoxic and fatal doses (38.7 to 306.8 mgm. of bismuth intramuscularly per kilo of weight) during periods of from one to seventy three days, all showed bismuth in the brain, the median being about 0.2 mgm. per 100 grams of brain. The brain content of bismuth noted cannot be due to the blood of the brain since the latter contains only-about 1.24% of its weight of blood.

It was not possible to obtain sufiicient cerebrospinal fluid from the animals for analysis but the spinal fluid of one rabbit gave a positive test for bismuth. In two moribund patients injected with iodobismuthite, the brain showed the presence of bismuth. Gt twenty four human subjects with cerebrospinal syphilis, or dementia praecox, twenty two, or about 92%, showed the presence of bismuth in the cerebrospinal fluid. In six patients, the bismuth was demonstrated in the cerebrospinal fluid at the end of 18 days after the in jection of the first dose of iodobismuthite in a concentration comparable to those secured after dosages necessary for anti-syphilitic action according to Lomholt in the Britishv Medical Journal, November 16, 1929, page 887. Bismuth was still present in the spinal fluid two weeks after the last dose was given. In comparison to the above results, thirteen out of seventeen cerebrospinal fluids from as many patients receiving total doses of from 0.2 to 16.9 grams of bismuth in the form of bismuth metal, potassium bismuth tartrate in oil or bismuth salicylate in oil in divided doses intra-muscularly showed no bismuth while two of the four positive tests secured were doubtful.

The products of the present invention have proved successful in clearing up the primary evidences of syphilis in animals although evidences of permanent cure could not be obtained since all the animals, including controls, died too early of intercurrent disease. In human patients, each patient receiving a 2 cc. injection containing 0.12 grams of iodo bismuthite every three days, evidences of elementary syphilis rapidly cleared up and disappeared. A positive demonstration of definite spirocheticidal action of anionic bismuth and of the bismuth in iodobismuthite has been secured.

For use in human patients, 2 cc. of the glycol solution of sodium iodobismuthite containing iodide should be injected intramuscularly, preferably into the gluteal muscle,

wice or thrice weekly, the parts receiving the injection being massaged after each injection and two days allowed free between injections. Up to ten successive injections may be given within four weeks as a single course of treatment and three to four courses with periods of about two weeks rest between courses. Bismuth has been definitely demonstrated in the cerebrospinal fluid after the course of ten injections and unless salivation or stomatitis develops the injections may be continued as outlined above. If salivation or stomatitis appear, the injections should be stopped and a short period ofrecovery allowed. These signs in the month are inevitable results of effective bismuth therapy and do not necessarily call for special treat ment unless severe.

I claim:

1. In a process of procuring a compound of bismuth in anionic form suitable for pharmacological and therapeutic use and free of impurities detrimental to such use, the steps of reacting a halogen salt with a bismuth salt in solution to form a salt of bismuthous acid and a substantially insoluble residue, filtering off the residue, evaporating the filtrate to form crystals of the salt of bismuthous acid, andv washing the salt with ether to remove impurities.

2. In a process of procuring sodium iodobismuthite suitable for pharmacological and therapeutic use and free of impurities detrimental to such use, the steps comprising reacting an excess of sodium iodide with a saturated solution of bismuth chloride in ethyl acetate to form sodium iodobismuthite and insoluble sodium chloride, filtering off the sodium chloride, and recovering the filtrate, evaporating the filtrate whereby crystals of sodium iodobismuthite are formed, and washing the crystals free of impurities.

3. In the process of procuring an alkalimetal halogen bismuthite suitable for pharmacological and therapeutic use and free of impurities detrimental to such use, the steps comprising reacting an excess of an alkali metal halide with a saturated solution of a bismuth halide in ethyl acetate to form a salt of bismuthous acid and a substantially insoluble residue, filtering off the residue, evaporating the filtrate to a. syrupy mass of crystals of the salt of bismuthous acid, and washing the crystals free of impurities with an organic solvent in which the crystals are less soluble than the impurities.

4:. In the process of procuring sodium iodobismuthite suitable for pharmacological and therapeutic use and free of impurities detrimental to such use, the steps comprising reacting sodium iodide with bismuth chloride in a solution of ethyl acetate to form the sodium iodobismuthite in solution and a substantially insoluble residue, refluxing the materials while the reaction proceeds, filtering oil the residue, evaporating the filtrate to a syrupy mass of crystals, filtering off the crystals, and washing them free of impurities with ether.

In testimony whereof, I have hereunto set my hand.

PAUL J HANZLIK. 

